The etiology of the age-associated pathophysiological changes of the hematopoietic system including the onset of anemia, diminished immune competence, and myelogenous disease development suggests profound losses of homeostatic control. Because homeostatic control is mediated by the activity of stem and progenitor cells, we propose that the homeostatic imbalances associated with the aged hematopoietic system result from alterations in the prevalence and/or functional capacity of hematopoietic stem and progenitor cells. The mechanisms driving loss of homeostatic control are poorly understood. The accumulation of somatic damage to cellular macromolecules is considered to be a major cause of cellular attrition and aging. In particular, the accumulation of DMA damage has been implicated as a central mechanism contributing to age-associated decline. In such a model of aging, DMA damage accrues in cells as they age and when accumulated damage becomes sufficiently disruptive can drive cells to 1) malignant transformation 2) cellular senescence, 3) programmed cell death, or 4) dysfunction. When this aging paradigm is considered within the context of stem cell biology, malignant transformation of stem cells would be predicted to result in increased cancer stem cell development, while stem cell senescence, cell death, and dysfunction would be predicted to lead to the diminished functional stem cell reserves. If stem cell depletion surpasses levels of stem cell self-renewal, then homeostatic failure - the physiological hallmark of aging - ensues. The objective of our research is to functionally characterize hematopoietic stem and progenitor cell aging to determine the extent to which dysfunction of these cells contributes to ageassociated pathophysiological decline, and to uncover the extent to which this dysfunction is driven by accumulated DMA damage.